In doing so, we will adhere learn more to the dual nature and function of skeletal stem cells, which act as progenitors, and act as non-progenitors [5]. Skeletal stem cells (also known as bone marrow-derived “mesenchymal” stem cells) generate all different lineages that together comprise the skeleton, and those lineages only. At the same time, they organize the vasculature of bone and bone marrow [2], establish the microenvironment for growth and differentiation of hematopoietic cells and establish the “niche” for hematopoietic stem cells (HSCs) [2], [3] and [6]. This notion comes originally

from studies using human cells and refined in vivo transplantation approaches [2], which were then confirmed in their key conceptual advances by a wealth of subsequent studies in the mouse, either using similar approaches, or genetic tools, or combinations of both [3], [7], [8], [9], [10] and [11]. At this time, efforts are being made to elucidate the potential diversity of local bone marrow territories with respect to hematopoietic functions, and the specific functions of putative (and as yet, GSK2126458 not conclusively identified) stromal subsets, or non-stromal cell types such as endothelial cells [10], [12] and [13] or neural cells [14] and [15]. However, recent data in the mouse directly support the general key concept that perivascular stromal skeletal stem cells (otherwise known as bone marrow-derived “mesenchymal” stem

cells [16]) act both as progenitors for skeletal tissues and as key players of the perivascular HME/niche also in the mouse [11] and [13]. The manner in which the function of skeletal stem cells is probed in the human system [i.e., heterotopic transplantation, also of clonal, single cell-derived populations [reviewed in [16]], to the effect of recapitulating the organogenesis of bone, illustrates these functions and their unique nature ADAMTS5 most effectively, in sharp contrast with other types of stem cells. Transplantation is the mainstay of stem cell biology. Transplantation of HSCs results in reconstitution of hematopoiesis; transplantation of epithelial stem cells in the reconstitution

of epithelial tissues; transplantation of pluripotent embryonic stem cells results in teratomas (i.e., in the chaotic admixture of all differentiated lineages); transplantation of skeletal stem cells results in the generation of different skeletal tissues, yes, but also in a highly coordinated, mutual organization of donor tissues with host tissues in a chimeric organoid [2], [5] and [6]. Skeletal stem cells are found in the bone marrow stroma. In situ, the bone marrow stroma is a highly elusive tissue, due to the simple fact that the key cell type, the adventitial reticular cell, escapes detection in conventional histological sections, and can only be visualized using a cytochemical stain (alkaline phosphatase) [17], [18] and [19] or immunocytochemical markers (e.g., CD146, CD105, CD90) [2].